Deregulated expression of molecules or signaling cascades involved in normal thymocyte development has been shown to lead to transformation. Perhaps the most striking example is the frequent detection of Notch activating mutations as initiating or cooperating events in human and mouse T-cell transformation. Both loss and gain of function studies have indicated that Wnt/[unreadable]-catenin signaling plays essential roles in thymocyte maturation and in particular during the double negative (DN) to double positive (DP) transition. More recent evidence indicates that conditional thymocyte specific stabilization of [unreadable]-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. T-cell transformation by [unreadable]-catenin requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional upregulation of c-Myc, whose activity is required for transformation. Interestingly, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized [unreadable]-catenin and remains low in the transformed cells indicating that Notch activation is not required or selected for in [unreadable]-catenin induced transformation. Thus, [unreadable]-catenin activation may provide a mechanism for T-cell transformation that does not depend on Notch activation. The proposed research will explore the potential role of [unreadable]-catenin in the etiology of human T-cell transformation, in particular cases that do not show Notch activation, and will investigate the molecular mechanism involved. Initially the dependence of transformed T-cells on [unreadable]-catenin will be investigated. Such cells that require [unreadable]-catenin activity for their maintenance will permit determination of the expression signature of [unreadable]-catenin in transformed T-cells and enable the interrogation of microarray data from primary samples for signs of deregulation of this pathway. Parallel studies will evaluate histologic material from T-cell lymphocytic lymphoma for evidence of activated nuclear [unreadable]-catenin. Events that cooperate with [unreadable]-catenin in T cell transformation will be explored by retroviral insertional mutagenesis, while the potential Rag dependent accumulation of chromosomal defects will be examined in lymphomas and pretransformed thymocytes by analysis of their genomic integrity. These approaches will evaluate whether deregulated activation of [unreadable]-catenin is etiologically linked to human T cell transformation and investigate whether this activity constitutes a suitable candidate for targeted therapy of these conditions. Relevance: Deregulation of cell signals that are responsible for the maturation of T-cells frequently leads to leukemia. The inappropriate activation of a signaling protein called 2-catenin causes transformation of T-cells in mice. Research proposed here aims at investigating whether 2-catenin is inappropriately activated in human T-cell leukemias and what other changes are required for the transformation of T-cells with activated 2-catenin. In this way this proposal will promote current understanding about the causes of T-cell leukemia and will provide new targets for the design of specialized therapies.